Asymmetric addition of organometallic compounds to carbonyls is a useful method for the production of chiral secondary/tertiary-alcohols. Typically for asymmetric synthesis, the active catalyst is generated in situ by the reaction of Lewis acid with chiral ligands. Addition of organometallic reagents to aldehydes and activated ketones has been achieved with excellent enantioselectivity. With inactivated ketones there has been some success, e.g., using salen 1 and camphanosulphonamide ligand 2.

Generally, stoichiometric amount of the promoters [Lewis acid, e.g., ZnR2 (R=alkyl/aryl), Zn(OTf)2, Cu(OTf)2, etc] is required for these asymmetric syntheses. Although, employing these promoters chiral alcohols has been obtained in high yields and ee upto 99%, they have limited applicability in industrial kale synthesis of the pharmaceutical intermediates, because they are expensive, difficult to store, difficult to handle, especially dialkyl zinc's are highly pyrophoric and require special modification to transfer the reagent. Moreover the liberated byproduct methane/ethane (when using ZnMe2/ZnEt2) are a concern on industrial scale synthesis.
To overcome this problem, herein we report an efficient synthesis of active organometallic catalyst formed in situ from chiral auxiliaries and Metal halides. For example ephedrine zincate 3 was obtained by first deprotonation of alcohol (achiral auxiliary) and N-pyrollidene norephidrine (chiral auxiliary) with a base (e.g. NaH); to the resulting alkoxides was added zinc halides (scheme 1A). The advantages include the low cost of zinc halides, ease of storing, handling and transfer. Moreover, the byproduct (sodium halides) formed has no safety issues. Based upon this concept, other active catalysts were synthesized using chiral ligands (such as binols, amino alcohols, amino alcohol derivatives, ethylenediamine, alkylated ethylene diamines and ethylenediamine derivatives in combination with metal source based on zinc and copper (scheme 1).


Using these chiral catalysts alkylation/alkynation of aldehydes afforded corresponding secondary alcohols (scheme-2),
while addition to ketones/β-ketoesters afforded corresponding tertiary alcohols (scheme 3A and 3B).

